Arterial stiffening (AS) is part of normal human aging and increases the risk of coronary artery disease and stroke. AS may be a primary stimulus for cardiac adaptations leading to age-related diastolic dysfunction which may lead to heart failure. We recently developed Doppler-based non-invasive techniques to determine pulse wave velocity (PWV), a measure of AS, in the anesthetized mouse. To our surprise, in preliminary data, we found the presence of age-related AS was not constant; it depended on the anesthetic agent used. Anesthetics associated with arterial smooth muscle dilation minimized age differences in PWV. Age-related AS has been attributed to age-associated changes in arterial structural proteins, collagen and elastin, and these would be unlikely to be altered by anesthesia. We hypothesize that elevated arterial smooth muscle tone contributes to AS in aging. We recognize anesthesia- induced alterations in blood pressure may confound our interpretation so blood pressure independent assessment of AS will be used.
Our specific aims are; 1) to refine and validate our techniques of measuring AS with PWV in the mouse, and 2) to assess the separate roles of smooth muscle tone, diastolic blood pressure, and structural protein changes in the aorta in age-associated AS in varying age and alpha-smooth muscle actin null (alpha-SMA-/-) mice (developed by our collaborators at Baylor). The alpha-SMA-/- has no PWV response to vasoactive agents, having no active (smooth muscle dependent) component of arterial stiffness and therefore may not develop age-related AS. We will evaluate the dependence of PWV on diastolic blood pressure by manipulating smooth muscle tone and blood pressure separately. Since our long term hypothesis is that AS (measured by increases in PWV) plays a pathogenic role in the diastolic dysfunction of aging, we will ultimately monitor cardiac function using methods we developed and validated. Should these efforts be successful, genetic manipulation of AS, its interaction with aging, and the end-effects of AS on the heart will be ripe for subsequent study.
| Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2011) Doppler velocity measurements from large and small arteries of mice. Am J Physiol Heart Circ Physiol 301:H269-78 |
| Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2008) Doppler estimation of reduced coronary flow reserve in mice with pressure overload cardiac hypertrophy. Ultrasound Med Biol 34:892-901 |
| Hartley, Craig J; Taffet, George E; Reddy, Anilkumar K et al. (2002) Noninvasive cardiovascular phenotyping in mice. ILAR J 43:147-58 |
| Hartley, C J; Reddy, A K; Madala, S et al. (2000) Hemodynamic changes in apolipoprotein E-knockout mice. Am J Physiol Heart Circ Physiol 279:H2326-34 |
